Journal articles: 'Cholinergic stimulation; Ulcerative colitis'

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Reardon, Colin, Ana Sanchez, Cory M. Hogaboam, and Derek M. McKay. "Tapeworm Infection Reduces Epithelial Ion Transport Abnormalities in Murine Dextran Sulfate Sodium-Induced Colitis." Infection and Immunity 69, no. 7 (July 1, 2001): 4417–23. http://dx.doi.org/10.1128/iai.69.7.4417-4423.2001.

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ABSTRACT The rat tapeworm Hymenolepis diminuta was used to test the hypothesis that helminth infection could modulate murine colitis. Mice were infected with five H. diminutacysticercoids, and colitis was evoked via free access to 4% (wt/vol) dextran sulfate sodium (DSS)-containing drinking water for 5 days. BALB/c mice were either infected with H. diminuta and 7 days later exposed to DSS (prophylactic strategy) or started on DSS and infected with H. diminuta 48 h later (treatment strategy). Naive andH. diminuta-only-infected mice served as controls. On autopsy, colonic segments were processed for histological examination and myeloperoxidase (MPO) measurement or mounted in Ussing chambers for assessment of epithelial ion transport. Cytokines (gamma interferon [IFN-γ], interleukin 12 [IL-12], and IL-10) were measured in serum and colonic tissue homogenates. DSS treatment resulted in reduced ion responses (indicated by short-circuit current [Isc]) to electrical nerve stimulation, the cholinergic agonist carbachol, and the adenylate cyclase activator forskolin compared to controls. H. diminuta infection, either prophylactic or therapeutic, caused a significant (P < 0.05) amelioration of these DSS-induced irregularities in stimulated ion transport. In contrast, the histopathology (i.e., mixed immune cell infiltrate, edema, and ulcerative damage) and elevated MPO levels that accompany DSS colitis were unaffected by concomitant H. diminuta infection. Similarly, there were no significant differences in levels of IFN-γ, IL-12, or IL-10 in serum or tissue from any of the treatment groups at the time of autopsy. We suggest that abolishment of colitis-induced epithelial ion transport abnormalities by H. diminuta infection provides proof-of-principle data and speculate that helminth therapy may provide relief of disease symptoms in colitis.

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Pai, Yu-Chen, and Linda Chia-Hui Yu. "Is “Cholinergic” Stimulus Useful for Ulcerative Colitis Treatment?" Digestive Diseases and Sciences 65, no. 1 (November 7, 2019): 6–8. http://dx.doi.org/10.1007/s10620-019-05933-8.

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Kemler, Marius A., Gerard A. M. Barendse, and Maarten van Kleef. "Relapsing ulcerative colitis associated with spinal cord stimulation." Gastroenterology 117, no. 1 (July 1999): 215–17. http://dx.doi.org/10.1016/s0016-5085(99)70570-6.

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Šventoraitytė, Jurgita, Aida Žvirblienė, Gediminas Kiudelis, Rimantas Žalinkevičius, Aurelija Žvirblienė, Antanas Praškevičius, Limas Kupčinskas, and Vytas Tamošiūnas. "Immune system alterations in patients with inflammatory bowel disease during remission." Medicina 44, no. 1 (January 16, 2008): 27. http://dx.doi.org/10.3390/medicina44010005.

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Objective. Perturbed immune homeostasis elicited by misbalanced production of proinflammatory and anti-inflammatory cytokines is characteristic of inflammatory bowel disease. The aim of this study was to evaluate cytokine profile in patients with different forms of inflammatory bowel disease – ulcerative colitis and Crohn’s disease – during clinical remission phase. Material and methods. Production of proinflammatory Th1 cytokines (tumor necrosis factoralpha (TNF-a), interferon-gamma (IFN-g)) and anti-inflammatory Th2 cytokines (interleukin- 10 (IL-10) and interleukin-13 (IL-13)) was analyzed in peripheral blood mononuclear cells of patients with inflammatory bowel disease (9 with ulcerative colitis and 9 with Crohn’s disease) and control subjects (n=11) by enzyme-linked immunosorbent assay (two-site ELISA). Results. The results of the study revealed that the level of TNF-a after stimulation with phytohemagglutinin in patients with Crohn’s disease was significantly higher in comparison to both patients with ulcerative colitis and controls (P<0.001 and P<0.01, respectively). The secretion of IFN-g both in patients with Crohn’s disease and ulcerative colitis was lower than that in controls (P=0.05 and P<0.01, respectively), but it normalized after stimulation with phytohemagglutinin. The levels of IL-10 and IL-13 were significantly (P<0.01) higher in patients with Crohn’s disease than in patients with ulcerative colitis and control group before and after stimulation with phytohemagglutinin. Conclusions. The results of our study provide evidence that in patients with inflammatory bowel disease, the imbalance between production of proinflammatory Th1 and anti-inflammatory Th2 cytokines persists even during remission of the disease, and disturbances of immune homeostasis are significantly more expressed in patients with Crohn’s disease than in patients with ulcerative colitis.

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Keates, S., A. C. Keates, E. Mizoguchi, A. Bhan, and C. P. Kelly. "Enterocytes are the primary source of the chemokine ENA-78 in normal colon and ulcerative colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 273, no. 1 (July 1, 1997): G75—G82. http://dx.doi.org/10.1152/ajpgi.1997.273.1.g75.

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Epithelial cell-derived neutrophil-activating protein-78 (ENA-78) is a neutrophil-directed C-X-C chemokine. We report that Caco-2 and T84 human intestinal epithelial cells produce ENA-78 after stimulation by interleukin (IL)-1 beta or tumor necrosis factor-alpha. Caco-2 cells show increased IL-8 production at 4-12 h and increased ENA-78 production at 8-24 h after cytokine stimulation. Immunohistochemical studies in normal human colon and in ulcerative colitis demonstrate ENA-78 immunoreactivity principally associated with crypt epithelial cells. Furthermore, human colonic tissues from patients with ulcerative colitis show elevated levels of ENA-78 mRNA (24-fold increase, P < 0.01) and protein (4-fold increase, P < 0.05) compared with normal controls. Thus ENA-78 is produced in normal colon and in ulcerative colitis and is predominantly of enterocyte origin. The kinetics of ENA-78 induction in human colon epithelial cell lines are delayed and prolonged compared with IL-8. We propose that ENA-78 and IL-8 serve complementary and sequential roles in neutrophil recruitment in ulcerative colitis. ENA-78 as an enterocyte-derived, neutrophil-activating chemokine may be especially important in neutrophil recruitment from the lamina propria into the epithelial layer.

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Snape, W. J., R. Williams, and P. E. Hyman. "Defect in colonic smooth muscle contraction in patients with ulcerative colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 261, no. 6 (December 1, 1991): G987—G991. http://dx.doi.org/10.1152/ajpgi.1991.261.6.g987.

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Patients with ulcerative colitis have decreased postprandial colonic contractions. The purpose of this study was to determine whether the smooth muscle from patients with ulcerative colitis responds abnormally in vitro to different stimuli. Circular colonic smooth muscle strips from patients with ulcerative colitis, acute diverticular disease, or adenocarcinoma were stretched to the optimal length and stimulated with electrical field stimulation (EFS), bethanechol, or increased concentrations of extracellular K+. The EFS-stimulated on-contraction was similar in each group, but the off-contraction was decreased in patients with colitis compared with patients with cancer (P less than 0.02) or diverticular disease (P less than 0.01). Bethanechol stimulated a dose-dependent colonic contraction, which was less in the strips from patients with colitis compared with cancer (P less than 0.02) or diverticular disease (P less than 0.05). The response to increased extracellular K+ was less in muscle from patients with colitis (P less than 0.01) than in the other tissues. Muscle from diverticular disease developed greater stress to K+ stimulation than did muscle from cancer (P less than 0.05). These studies suggest that there is a decrease in the force of muscle contraction in colonic muscle obtained from patients with colitis compared with normal muscle resected from patients with cancer or with muscle associated with diverticular disease of the colon. The similar relatively low amplitude of the on-contraction in each group suggests the physiological release of an inhibitory neurotransmitter.

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Deng, Quan-Jun, Ding-Jing Deng, Jin Che, Hai-Rong Zhao, Jun-Jie Yu, and Yong-Yu Lu. "Hypothalamic paraventricular nucleus stimulation reduces intestinal injury in rats with ulcerative colitis." World Journal of Gastroenterology 22, no. 14 (2016): 3769. http://dx.doi.org/10.3748/wjg.v22.i14.3769.

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Finnie, Ian A., Barry J. Campbell, Barry A. Taylor, Jeremy D. Milton, Sherif K. Sadek, Lu-Gang Yu, and Jonathan M. Rhodes. "Stimulation of Colonic Mucin Synthesis by Corticosteroids and Nicotine." Clinical Science 91, no. 3 (September 1, 1996): 359–64. http://dx.doi.org/10.1042/cs0910359.

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1. We speculated that corticosteroids might cause beneficial stimulation of mucus synthesis, since this is a known action of carbenoxolone, itself a corticosteroid, and has also been proposed as a possible mechanism for the protective effect of smoking on ulcerative colitis. We have therefore compared the effects of corticosteroids including carbenoxolone, and nicotine on mucin synthesis, assessed by incorporation of N-[3H]acetylglucosamine into mucin by colonic epithelial biopsies in culture. 2. In histologically normal biopsies from the left colon, hydrocortisone and prednisolone caused a very marked concentration-dependent increase in mucin synthesis, with maximal effect (580 and 300% of control values respectively) at 6 μmol/l [P < 0.001, n = 35 biopsies (seven patients)] and 1.5 μmol/l [P < 0.001, n = 35 (seven patients)] respectively. The maximal effect of hydrocortisone was significantly greater than that of prednisolone (P < 0.05). Carbenoxolone, 0.17 mmol/l, also increased mucin synthesis in the left colon by 242% [P < 0.05, n =15 (three patients)]. In contrast, these corticosteroids caused only a small, non-significant increase in mucin synthesis in the histologically normal right colon; fludrocortisone, 2 and 20 μmol/l, and aldosterone, 0.1–10 μmol/l, had no effect. Nicotine significantly increased mucin synthesis (180–220% of control values) between 62.5 nmol/l and 6.25 μmol/l (P < 0.05 at all concentrations) in both the right and left colon. In biopsies from the relatively uninvolved right colon of patients with ulcerative colitis, corticosteroids and nicotine caused relatively smaller increases in mucin synthesis. 3. The marked stimulation of mucin synthesis by corticosteroids suggests that this may account, at least in part, for their therapeutic effect in ulcerative colitis.

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Barbara, Giovanni, Roberto de Giorgio, Vincenzo Stanghellini, Paolo Gionchetti, Massimo Campieri, and Roberto Corinaldesi. "Relapsing ulcerative colitis after spinal cord stimulation: A case of intestinal neurogenic inflammation?" Gastroenterology 117, no. 5 (November 1999): 1256–57. http://dx.doi.org/10.1016/s0016-5085(99)70425-7.

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Shifrin, Helena, Odelia Mouhadeb, Nathan Gluck, Chen Varol, and Marta Weinstock. "Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates." Journal of Neuroimmune Pharmacology 12, no. 3 (March 7, 2017): 484–91. http://dx.doi.org/10.1007/s11481-017-9735-8.

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Tomita, Ryouichi, Keimei Munakata, and Katsuhisa Tanjoh. "Role of non-adrenergic non-cholinergic inhibitory nerves in the colon of patients with ulcerative colitis." Journal of Gastroenterology 33, no. 1 (January 10, 1998): 48–52. http://dx.doi.org/10.1007/pl00009965.

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Wang, Xiaomei, Shuang Zhou, Wei Yao, Hua Wan, Huangan Wu, Luyi Wu, Huirong Liu, Xuegui Hua, and Peifeng Shi. "Effects of Moxibustion Stimulation on the Intensity of Infrared Radiation of Tianshu (ST25) Acupoints in Rats with Ulcerative Colitis." Evidence-Based Complementary and Alternative Medicine 2012 (2012): 1–13. http://dx.doi.org/10.1155/2012/704584.

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ST25 is a key acupoint used in the treatment of ulcerative colitis by moxibustion stimulation, but the biophysical mechanism underlying its effects is still unknown. The aim of the present study was to explore the biophysical properties of ST25 acupoint stimulated by moxibustion in a rat model of ulcerative colitis. The infrared radiation intensity of fourteen wavelengths of ST25 showed significant differences between the normal and model control groups. The intensity of infrared radiation of forty wavelengths showed significant differences compared with the corresponding control points in normal rats. The intensity of infrared radiation of twenty-eight wavelengths showed significant differences compared with the corresponding control points in model rats. The intensity of infrared radiation of nine wavelengths in the herb-partition moxibustion group, eighteen wavelengths in the ginger-partition moxibustion group, seventeen wavelengths in the garlic-partition moxibustion group, and fourteen wavelengths in the warming moxibustion group of the left ST25 showed significant differences compared with that of the model control group. For the right-hand-side ST25, these values were 33, 33, 2, and 8 wavelengths, respectively. This indicated that one possible biophysical mechanism of moxibustion on ST25 in ulcerative colitis model rats might involve changes in the intensity of infrared radiation of ST25 at different wavelengths.

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Yao, Dianbo, Ming Dong, Chaoliu Dai, and Shuodong Wu. "Inflammation and Inflammatory Cytokine Contribute to the Initiation and Development of Ulcerative Colitis and Its Associated Cancer." Inflammatory Bowel Diseases 25, no. 10 (July 9, 2019): 1595–602. http://dx.doi.org/10.1093/ibd/izz149.

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Abstract Dysregulated inflammatory responses play a pivotal role in the initiation, development, and progression of tumors, as demonstrated by the association between ulcerative colitis and the increased risk of colon carcinoma. In this review, the underlying mechanisms for the initiation and development of ulcerative colitis and colitis-associated cancer are described, mainly focusing on the inflammation and inflammatory cytokine. Disruption of the intestinal mucosal barrier and bacterial invasion resulted in intestinal inflammation; and further TLR4/NF-κB stimulation in intestinal epithelial cells, inflammatory cell infiltration, and inflammatory cytokine release all confer survival advantages to or promote abnormal proliferation in susceptible cells. Importantly, the respective roles of TLR4/NF-κB, TNF–α, and IL-6 in intestinal epithelial cells and inflammatory cells are summarized in detail. A thorough understanding of these molecular mechanisms may help researchers and clinicians to explore novel approaches for the prevention and treatment of colitis-associated cancer.

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Xu, Zhuoni, Baoping Wei, Yanting Qiu, and Tao Zhang. "Altered Salivary Alpha-Amylase Secretion in Patients with Ulcerative Colitis." Gastroenterology Research and Practice 2018 (2018): 1–6. http://dx.doi.org/10.1155/2018/4203737.

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Purpose. Patients with ulcerative colitis (UC) frequently present with psychological disturbances as well as dysfunctions of autonomic nervous system (ANS). Salivary alpha-amylase (sAA) secretion is predominantly controlled by sympathetic nervous activity, while salivary fluid secretion is by parasympathetic nervous activity. Thus, it is speculated that alterations of salivary secretion may be addressed in UC populations. Methods. Thirty-five UC patients as well as 32 age- and sex-matched healthy controls were enrolled. Saliva samples before and after citric acid stimulation were collected from each participant, and salivary flow rate (SFR) was calculated accordingly. Western blotting and quantitative PCR were applied to measure the sAA level and sAA gene (AMY1) copy number, respectively. The psychological disorders, anxiety and depression, were evaluated by the scoring system of Hospital Anxiety and Depression Scale (HADS) for each participant. Results. We observed robustly increased prevalence of anxiety (p<0.001) as well as depression (p<0.001) in UC patients relative to controls. Interestingly, we detected elevated basal (p=0.015) and stimulated (p=0.021) sAA levels in the UC populations compared to controls. However, no differences were found for basal (p=0.643) or stimulated (p=0.402) SFR between the two study groups. Besides, AMY1 gene copy number was comparable between UC patients and controls. Conclusions. Our results reveal an overactivity of the sympathetic nervous system and a normal activity of the parasympathetic nervous system in the UC population.

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Nii, Kohichiroh, Kaoru Okazaki, Hitoshi Okada, and Toru Kuboi. "Maternal mesalazine-induced neonatal gastrointestinal bleeding." BMJ Case Reports 14, no. 4 (April 2021): e238743. http://dx.doi.org/10.1136/bcr-2020-238743.

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Ulcerative colitis often develops in the reproductive age women and can cause exacerbation by pregnancy. Mesalazine (5-aminosalicylic acid) is recommended as a safe anti-inflammatory drug during pregnancy. However, maternal mesalazine is transferred to the fetus through the placenta and may cause allergic events. A pregnant woman with severe ulcerative colitis was treated with a dose of mesalazine 4,000 mg/day from early gestation to delivery. Immediately after birth, the preterm neonate vomited bloody contents and discharged massive gross haematochezia. Serum concentrations of mesalazine and its main metabolite were high in the mother and the umbilical cord. Faecal eosinophils and drug-induced lymphocyte stimulation test suggested possibility that sensitisation with mesalazine in utero caused allergic enterocolitis like food protein-induced allergic proctocolitis. Maternal mesalazine has a potential of fetal sensitisation and cause allergic disease.

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Robinson, Ainsley M., Ahmed A. Rahman, Simona E. Carbone, Sarron Randall-Demllo, Rhiannon Filippone, Joel C. Bornstein, Rajaraman Eri, and Kulmira Nurgali. "Alterations of colonic function in the Winnie mouse model of spontaneous chronic colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 312, no. 1 (January 1, 2017): G85—G102. http://dx.doi.org/10.1152/ajpgi.00210.2016.

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The Winnie mouse, carrying a missense mutation in Muc2, is a model for chronic intestinal inflammation demonstrating symptoms closely resembling inflammatory bowel disease (IBD). Alterations to the immune environment, morphological structure, and innervation of Winnie mouse colon have been identified; however, analyses of intestinal transit and colonic functions have not been conducted. In this study, we investigated in vivo intestinal transit in radiographic studies and in vitro motility of the isolated colon in organ bath experiments. We compared neuromuscular transmission using conventional intracellular recording between distal colon of Winnie and C57BL/6 mice and smooth muscle contractions using force displacement transducers. Chronic inflammation in Winnie mice was confirmed by detection of lipocalin-2 in fecal samples over 4 wk and gross morphological damage to the colon. Colonic transit was faster in Winnie mice. Motility was altered including decreased frequency and increased speed of colonic migrating motor complexes and increased occurrence of short and fragmented contractions. The mechanisms underlying colon dysfunctions in Winnie mice included inhibition of excitatory and fast inhibitory junction potentials, diminished smooth muscle responses to cholinergic and nitrergic stimulation, and increased number of α-smooth muscle actin-immunoreactive cells. We conclude that diminished excitatory responses occur both prejunctionally and postjunctionally and reduced inhibitory purinergic responses are potentially a prejunctional event, while diminished nitrergic inhibitory responses are probably due to a postjunction mechanism in the Winnie mouse colon. Many of these changes are similar to disturbed motor functions in IBD patients indicating that the Winnie mouse is a model highly representative of human IBD. NEW & NOTEWORTHY This is the first study to provide analyses of intestinal transit and whole colon motility in an animal model of spontaneous chronic colitis. We found that cholinergic and purinergic neuromuscular transmission, as well as the smooth muscle cell responses to cholinergic and nitrergic stimulation, is altered in the chronically inflamed Winnie mouse colon. The changes to intestinal transit and colonic function we identified in the Winnie mouse are similar to those seen in inflammatory bowel disease patients.

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Wardle, T. D., and L. A. Turnberg. "Potential Role for Interleukin-1 in the Pathophysiology of Ulcerative Colitis." Clinical Science 86, no. 5 (May 1, 1994): 619–26. http://dx.doi.org/10.1042/cs0860619.

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1. Biopsies of colonic mucosa from patients with ulcerative colitis liberated more interleukin-1β, prostaglandin E2, leukotriene C4 and platelet-activating factor into the medium in which they were cultured than biopsies from patients with irritable bowel syndrome and histologically normal mucosa. 2. Addition of interleukin-1 stimulated release of greater quantities of all these inflammatory mediators, including interleukin-1 itself, from inflamed and normal mucosa. 3. Blockade of cyclo-oxygenase with indomethacin or of lipoxygenase with ICI 207968 or of phospholipase A2 with mepacrine inhibited release of prostaglandin E2 or leukotriene C4 or both of these plus platelet-activating factor, respectively. 4. Interleukin-1 stimulated the short-circuit current across isolated rat colonic mucosa mounted in flux chambers in a dose-dependent manner (Km 2 × 10−11 mol/l). This stimulation was markedly inhibited by the removal of chloride from the bathing media. 5. Indomethacin or ICI 207968 inhibited the short-circuit current response to interleukin-1 and a combination of these antagonists produced a greater inhibition. Mepacrine caused an even greater inhibition whereas tetrodotoxin plus mepacrine inhibited the current completely. 6. These data indicate that interleukin-1, released in excess from inflamed colonic mucosa, stimulates the release of a range of inflammatory mediators as well as of more interleukin-1. It probably acts by stimulating phospholipase A2 in inflammatory cells, probably lymphocytes, and can do so in normal and inflamed mucosa. Since, in rat colonic mucosa it stimulated an electrical response in very low concentrations, it is feasible that it is involved in the chloride secretion, and hence the diarrhoea, which may occur in inflammatory reactions. Hence treatment with mepacrine seems a prospect worth pursuing.

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Jönsson, Maria, Örjan Norrgård, and Sture Forsgren. "Presence of a marked nonneuronal cholinergic system in human colon: Study of normal colon and colon in ulcerative colitis." Inflammatory Bowel Diseases 13, no. 11 (November 2007): 1347–56. http://dx.doi.org/10.1002/ibd.20224.

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Iakovlev, A. A., A. Volkov, G. Tarasova, and A. Zubova. "P039 New molecular markers of the development of ulcerative colitis." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S151. http://dx.doi.org/10.1093/ecco-jcc/jjab076.168.

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Abstract Background The mechanisms of ulcerative colitis (UC) progression require detailed study. Modern achievements of proteomic methods of analysis are ideal for research that is free from hypotheses and allows us to define molecular characteristics of inflammation in colon mucosa of UC patients. Methods The study was comparative cohort with parallel design and included 88 patients (range from 22 to 35 years, 37 men and 51 women): 53 (60.2%) pancolitis and 35 (39.8%) left-sided UC, mild and moderate activity. The control group included 30 healthy individuals. Biosamples of colon mucosa in patients with UC in the active stage and in healthy persons were received by ileocolonoscopy with colon mucosa biopsy. The separation of individual proteins of colon mucosa was based on technologies of IEF, SDS-PAGE, 2DPAGE, by standard sets (MB-HIC C8 Kit, MB-IMAC Cu, MB-Wax Kit, «Bruker», USA). Automated mass spectrometry imaging was performed by MALDI-TOF-MS/MS, Ultraflex II, «Bruker», USA). The data of the molecular interactions and functional features of proteins were received with STRING 10.0 database. Results We identified following functional groups of peptides and proteins in molecular patterns of colon mucosa in UC patients: SMAD family member 2 (SMAD2) activates the transcription of TFG1β, that leads to specific regulation of the CCN2 gene in cells and the development of fibrosis in colon submucosa in UC patients; the stimulation of the expression of apoС-III in affected colon mucosa in UC is associated with the activation of the FOXO1 signaling pathway that supports inflammatory processes in colon mucosa; the second small heat shock protein (HSP2) controls the apoptosis of colonocytes, is also responsible for the mucosa resistance to therapeutic strategies; caspase 8 protects colonocytes from TNFα-induced cell death through a necroptosis mechanism via the blockade of the RIP3 expression; the expression of prohibitin maintains optimal activity of the electronic transport chain through the activity of transcription factor STAT3 and the decrease in the TNFα expression; significant decrease of the PPARγ expression promotes the activation of STAT and AP-1 signaling pathways, which promotes the activity of immune and inflamation processes in colon mucosa and a significant increase in the NF-kB expression in colon mucosa is associated with the activation of TNFα and IL-1, which promotes the increase of immune processes in colon mucosa. Conclusion Bioinformatics analysis revealed the presence of molecules that are the participants in the universal pathways of UC in the active stage, and the molecular interactions involved. This information may provide new avenues for the development of novel diagnostic tests for UC.

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Jones, S. C., J. E. Crabtree, B. J. Rembacken, M. F. Dixon, L. K. Trejdosiewicz, J. T. Hicher, and A. T. R. Axon. "Mucosal Interleukin-6 Secretion in Ulcerative Colitis: Effects of Anti-Inflammatory Drugs and T-Cell Stimulation." Scandinavian Journal of Gastroenterology 29, no. 8 (January 1994): 722–28. http://dx.doi.org/10.3109/00365529409092500.

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Vigna, Steven R. "Nicotine InhibitsClostridium difficileToxin A-Induced Colitis but Not Ileitis in Rats." International Journal of Inflammation 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/4705065.

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Nicotine is protective in ulcerative colitis but not Crohn’s disease of the small intestine, but little is known about the effects of nicotine onClostridium difficiletoxin A-induced enteritis. Isolated ileal or colonic segments in anesthetized rats were pretreated with nicotine bitartrate or other pharmacological agents before intraluminal injection of toxin A. After 3 hours, the treated segments were removed and inflammation was assessed. Nicotine biphasically inhibited toxin A colitis but not ileitis. Pretreatment with the nicotinic receptor antagonist, hexamethonium, blocked the effects of nicotine. Pretreating the colonic segments with hexamethonium before toxin A administration resulted in more inflammation than seen with toxin A alone, suggesting that a tonic nicotinic anti-inflammatory condition exists in the colon. Nicotine also inhibited toxin A-induced increased colonic concentrations of the TRPV1 (transient receptor potential vanilloid subtype 1) agonist, leukotriene B4(LTB4), and release of the proinflammatory neuropeptide, substance P. Pretreatment with nicotine did not protect against direct TRPV1-mediated colitis caused by intraluminal capsaicin. Nicotinic cholinergic receptors tonically protect the colon against inflammation and nicotine inhibits toxin A colitis but not toxin A ileitis in rats in part by inhibition of toxin A-induced activation of TRPV1 by endogenous TRPV1 agonists such as LTB4.

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AlSharari, Shakir D., Deniz Bagdas, Hamid I. Akbarali, Patraic A. Lichtman, Erinn S. Raborn, Guy A. Cabral, F. Ivy Carroll, Elizabeth A. McGee, and M. Imad Damaj. "Sex Differences and Drug Dose Influence the Role of the α7 Nicotinic Acetylcholine Receptor in the Mouse Dextran Sodium Sulfate-Induced Colitis Model." Nicotine & Tobacco Research 19, no. 4 (October 25, 2016): 460–68. http://dx.doi.org/10.1093/ntr/ntw245.

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Abstract Introduction: α7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. Methods: Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. Results: Male, but not female, α7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses. Conclusions: Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse. Implications: Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.

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Chen, Zhengxin, Min Ni, Jing Li, Sumin Zhang, Hao Chen, Min Li, Yanni Liu, Zhimin Fan, and Jiande Chen. "Su1616 – Anti-Inflammatory Effects and Mechanisms of Sacral Nerve Stimulation Performed Via Acupuncture Needles on Ulcerative Colitis." Gastroenterology 156, no. 6 (May 2019): S—585. http://dx.doi.org/10.1016/s0016-5085(19)38355-6.

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Guo, Jie, Haifeng Jin, Zhaohong Shi, Xuhang Li, Pankaj J. Pasricha, Jieyun Yin, and Jiande Chen. "453 Anti-Inflammatory Effects and Mechanisms of Sacral Nerve Stimulation on TNBS-Induced Ulcerative Colitis in Rats." Gastroenterology 150, no. 4 (April 2016): S98. http://dx.doi.org/10.1016/s0016-5085(16)30438-3.

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Østvik, Ann Elisabet, Tarjei Dahl Svendsen, Atle van Beelen Granlund, Berit Doseth, Helene Kolstad Skovdahl, Ingunn Bakke, Silje Thorsvik, et al. "Intestinal Epithelial Cells Express Immunomodulatory ISG15 During Active Ulcerative Colitis and Crohn’s Disease." Journal of Crohn's and Colitis 14, no. 7 (February 5, 2020): 920–34. http://dx.doi.org/10.1093/ecco-jcc/jjaa022.

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Abstract Background and Aims Intestinal epithelial cells [IECs] secrete cytokines that recruit immune cells to the mucosa and regulate immune responses that drive inflammation in inflammatory bowel disease [IBD]. However, experiments in patient-derived IEC models are still scarce. Here, we aimed to investigate how innate immunity and IEC-specific pattern recognition receptor [PRR] signalling can be involved in an enhanced type I interferon [IFN] gene signature observed in colon epithelium of patients with active IBD, with a special focus on secreted ubiquitin-like protein ISG15. Methods Gene and protein expression in whole mucosa biopsies and in microdissected human colonic epithelial lining, in HT29 human intestinal epithelial cells and primary 3D colonoids treated with PRR-ligands and cytokines, were detected by transcriptomics, in situ hybridisation, immunohistochemistry, western blots, and enzyme-linked immunosorbent assay [ELISA]. Effects of IEC-secreted cytokines were examined in human peripheral blood mononuclear cells [PBMCs] by multiplex chemokine profiling and ELISA. Results The type I IFN gene signature in human mucosal biopsies was mimicked in Toll-like receptor TLR3 and to some extent tumour necrosis factor [TNF]-treated human IECs. In intestinal biopsies, ISG15 expression correlated with expression of the newly identified receptor for extracellular ISG15, LFA-1 integrin. ISG15 was expressed and secreted from HT29 cells and primary 3D colonoids through both JAK1-pSTAT-IRF9-dependent and independent pathways. In experiments using PBMCs, we show that ISG15 releases IBD-relevant proinflammatory cytokines such as CXCL1, CXCL5, CXCL8, CCL20, IL1, IL6, TNF, and IFNγ. Conclusions ISG15 is secreted from primary IECs upon extracellular stimulation, and mucosal ISG15 emerges as an intriguing candidate for immunotherapy in IBD.

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Noronha, R., H. Akbarali, A. Malykhina, R. D. Foreman, and Beverley Greenwood-Van Meerveld. "Changes in urinary bladder smooth muscle function in response to colonic inflammation." American Journal of Physiology-Renal Physiology 293, no. 5 (November 2007): F1461—F1467. http://dx.doi.org/10.1152/ajprenal.00311.2007.

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Visceral organ “cross talk” is suspected to contribute to multiorgan symptomatology found in conditions such as irritable bowel syndrome and interstitial cystitis. The goal of the present study was to investigate the short- and long-term effects of acute colitis on bladder detrusor muscle contractility. We hypothesized that inflammation of the colon leads to changes in bladder function via direct changes in detrusor smooth muscle contractility. In this study, colonic inflammation was induced in male rats via an enema of trinitrobenzenesulfonic acid (TNBS) (50 mg/kg, 0.5 ml, 25% ethanol). Colitis was confirmed using gross morphology, histology, and measurements of myeloperoxidase activity. Saline enema-treated rats served as controls. Three, 15, and 30 days postenema treatment, bladder detrusor muscle contractility was investigated in response to electrical field stimulation (EFS), cholinergic agonism with carbachol (CCh), and KCl. During active colonic inflammation ( day 3 post-TNBS enema), the bladder detrusor muscle appeared normal and showed no significant inflammation. However, abnormalities in bladder detrusor muscle contractility occurred in response to EFS and CCh but not KCl. During and after recovery from colonic inflammation ( days 15 and 30 post-TNBS enema), changes in bladder detrusor muscle contractility in response to EFS and CCh returned to control levels. We found that a transient colonic inflammatory insult significantly attenuates the amplitude of bladder detrusor muscle contractions in vitro, at least in part, through changes in cholinergic innervation, which are reversible after recovery from the colitis.

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Li, Xiao, Lin Cai, Hua Xu, Chong Geng, Jing Lu, Liping Tao, Dan Sun, Fayez K. Ghishan, and Chunhui Wang. "Somatostatin regulates NHE8 protein expression via the ERK1/2 MAPK pathway in DSS-induced colitis mice." American Journal of Physiology-Gastrointestinal and Liver Physiology 311, no. 5 (November 1, 2016): G954—G963. http://dx.doi.org/10.1152/ajpgi.00239.2016.

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Previous studies reported that administration of somatostatin (SST) to human patients mitigated their diarrheal symptoms. Octreotide (an analog of SST) treatment in animals resulted in upregulation of sodium/hydrogen exchanger 8 (NHE8). NHE8 is important for water/sodium absorption in the intestine, and loss of NHE8 function results in mucosal injury. Thus we hypothesized that NHE8 expression is inhibited during colitis and that SST treatment during pathological conditions can restore NHE8 expression. Our data showed for the first time that NHE8 is expressed in the human colonic tissue and that NHE8 expression is decreased in ulcerative colitis (UC) patients. We also found that octreotide could stimulate colonic NHE8 expression in colitic mice. Furthermore, the somatostatin receptor 2 (SSTR2) agonist seglitide and the somatostatin receptor 5 (SSTR5) agonist L-817,818 could restore NHE8 expression via its role in suppressing ERK1/2 phosphorylation. Our study uncovered a novel mechanism of SST stimulation of NHE8 expression in colitis.

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Linehan, John D., George Kolios, Vassilis Valatas, Duncan A. F. Robertson, and John Westwick. "Effect of corticosteroids on nitric oxide production in inflammatory bowel disease: are leukocytes the site of action?" American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 2 (February 2005): G261—G267. http://dx.doi.org/10.1152/ajpgi.00336.2004.

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Nitric oxide (NO) production is increased in the human colonic mucosa in intestinal inflammation. We examined the effect of corticosteroids and the role of mononuclear cells in this production. Colonic biopsies from patients with ulcerative colitis and normal controls were cultured with either budesonide or prednisolone in the presence of proinflammatory cytokines. Human mixed mononuclear cells (MMCs) were cocultured with HT-29 cells stimulated with IFN-γ and LPS in the presence or absence of corticosteroids. Nitrite production was measured in supernatants by a modification of the Griess reaction, and inducible NO synthase (iNOS) mRNA expression was studied in colonic tissue by RT-PCR. Both steroids significantly suppressed the nitrite production and iNOS mRNA expression in inflamed colonic biopsies from ulcerative colitis patients and in cytokine-stimulated normal colonic biopsies but not in cytokine-stimulated HT-29 cells. Nitrite production by HT-29 cells was significantly increased ( P < 0.01) in cocultures with MMCs stimulated with IFN-γ and LPS. The presence of either prednisolone or budesonide significantly ( P < 0.01) suppressed nitrite production from cocultures of HT-29 cells and MMCs but not from cultures of HT-29 cells stimulated with conditioned media from activated MMCs. Interestingly, stimulation of HT-29 with conditioned media from MMCs pretreated with steroids before stimulation with LPS and IFN-γ induced a significantly ( P < 0.01) lower nitrite production. These results suggest that the inhibitory effect of corticosteroids on the NO production in the intestinal inflammation might be via the inhibition of MMC-produced mediators responsible for NO production by colonic epithelial cells.

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Kwon, John H., Andrew C. Keates, Pauline M. Anton, Maria Botero, Jeffrey D. Goldsmith, and Ciarán P. Kelly. "Topical antisense oligonucleotide therapy against LIX, an enterocyte-expressed CXC chemokine, reduces murine colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 289, no. 6 (December 2005): G1075—G1083. http://dx.doi.org/10.1152/ajpgi.00073.2005.

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Epithelial neutrophil-activating peptide-78 (ENA-78), a member of the CXC chemokine subfamily, is induced by inflammatory cytokines in human colonic enterocyte cell lines and increased in the colon of patients with inflammatory bowel disease (IBD). Lipopolysaccharide-induced CXC-chemokine (LIX) was recently identified as the murine homolog of ENA-78. Here we show that, similar to ENA-78, inflammatory cytokine stimulation of a murine colonic epithelial cell line, MODE-K, results in increased LIX expression. Consistent with the expression pattern of ENA-78 in IBD, LIX expression is significantly increased in mice with colitis induced by the ingestion of dextran sodium sulfate (DSS). Treating mice with antisense oligonucleotides to LIX via rectal enema delivery before DSS treatment results in colonic enterocyte uptake and a significant reduction in neutrophil infiltration and severity of colitis. These findings indicate that LIX plays an integral role in the pathogenesis of DSS-induced colitis. Similarly, enterocyte-derived CXC chemokines may play a key role in regulating neutrophil recruitment and intestinal injury in IBD. The intracolonic administration of ENA-78 antisense oligonucleotides may be effective in treating distal ulcerative colitis in humans.

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Gay, Jérôme, Efi Kokkotou, Michael O’Brien, Charalabos Pothoulakis, and Katia P. Karalis. "Corticotropin-Releasing Hormone Deficiency Is Associated with Reduced Local Inflammation in a Mouse Model of Experimental Colitis." Endocrinology 149, no. 7 (April 10, 2008): 3403–9. http://dx.doi.org/10.1210/en.2007-1703.

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CRH, the hypothalamic component of the hypothalamic-pituitary adrenal axis, attenuates inflammation through stimulation of glucocorticoid release, whereas peripherally expressed CRH acts as a proinflammatory mediator. CRH is expressed in the intestine and up-regulated in patients with ulcerative colitis. However, its pathophysiological significance in intestinal inflammatory diseases has just started to emerge. In a mouse model of acute, trinitrobenzene sulfonic acid-induced experimental colitis, we demonstrate that, despite low glucocorticoid levels, CRH-deficient mice develop substantially reduced local inflammatory responses. These effects were shown by histological scoring of tissue damage and neutrophil infiltration. At the same time, CRH deficiency was found to be associated with higher serum leptin and IL-6 levels along with sustained anorexia and weight loss, although central CRH has been reported to be a strong appetite suppressor. Taken together, our results support an important proinflammatory role for CRH during mouse experimental colitis and possibly in inflammatory bowel disease in humans. Moreover, the results suggest that CRH is involved in homeostatic pathways that link inflammation and metabolism.

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Tomita, Ryouichi, Kiminobu Sugito, Kenichi Sakurai, Shigeru Fujisaki, and Tsugumichi Koshinaga. "Sacral Nerve Function in Child Patients After Ileal J-Pouch-Anal Anastomosis for Ulcerative Colitis." International Surgery 99, no. 5 (September 1, 2014): 506–11. http://dx.doi.org/10.9738/intsurg-d-13-00043.1.

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Abstract To clarify the neurological function of the puborectalis muscle (PM) in child patients with soiling after ileal J-pouch-anal anastomosis (IPAA) for ulcerative colitis (UC), we examined the terminal motor latency in the sacral nerves that regulate the PM. Eight patients after IPAA for UC were studied (6 males and 2 females aged 11 to 13 years with a mean age of 12.8 years). All patients 6 months after IPAA showed soiling (group A) and these patients showed continence at 2 years after IPAA (group B). Group C serving as controls consisted of 16 subjects (10 males and 6 females aged 12 to 17 years with a mean age of 14.4 years). Left- and right-sided sacral nerve terminal motor latency (SNTML) tests were performed at 6 months and 2 years after IPAA in order to measure the latency of the response in the bilateral PM following magnetic stimulation of sacral nerve root segments 2 to 4 (S2–S4) of the spinal column overlying the cauda equina. The following results were obtained. (1) Right-sided SNTML: group A exhibited significant prolongation compared with groups B and C (P < 0.0001 and P < 0.0001, respectively). There was no significant difference between groups B and C (P = 0.2329). (2) Left-sided SNTML: group A exhibited significant prolongation compared with groups B and C (P = 0.0002 and P < 0.0001, respectively). There was no significant difference between groups B and C (P = 0.2315). Note that significant differences were not established between SNTML values measured on the right and left sides. Soiling in child patients 6 months after IPAA may be caused by damage to the bilateral sacral nerves during the operation. However, the damage to the sacral motor nerve improves within 2 years after IPAA.

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Marshall, Ryan, Ian Taylor, Christopher Lahr, Thomas L. Abell, Ingrid Espinoza, Nitin K. Gupta, and Christian R. Gomez. "Bioelectrical Stimulation for the Reduction of Inflammation in Inflammatory Bowel Disease." Clinical Medicine Insights: Gastroenterology 8 (January 2015): CGast.S31779. http://dx.doi.org/10.4137/cgast.s31779.

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Crohn's disease and ulcerative colitis are the primary inflammatory bowel diseases (IBDs) affecting the gastrointestinal tract. The current therapy aims at decreasing inflammation and reducing symptoms. This typically requires immune suppression by steroids, thiopurines, methotrexate, or tumor necrosis factor inhibitors. Patients may be unreceptive to medical therapy, and some may discontinue the treatment due to adverse effects. Noninvasive, transcutaneous vagus nerve stimulation (VNS) is currently used as a treatment for depression and epilepsy, and it is being investigated for the treatment of conditions such as multiple sclerosis, migraines, and Alzheimer's disease. Recent studies have demonstrated the importance of splenic and vagus nerve functions in the inflammatory process through the production of certain cytokines. We hypothesize that using transcutaneous VNS via the auricular afferent branch could achieve a selective anti-inflammatory effect on the intestinal wall. This review examines the possibility of using vagal stimulators as a therapy for IBD. This could open the door to novel treatments for numerous vagally mediated diseases characterized by poor responses to current therapies.

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Ford, Jason C., Louis D. Wadsworth, and Kirk R. Schultz. "ADP Signaling Defect in Children with Severe Acquired Aplastic Anemia: A Potential Common Pathway for Development of Aplastic Anemia." Blood 104, no. 11 (November 16, 2004): 3934. http://dx.doi.org/10.1182/blood.v104.11.3934.3934.

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Abstract Severe Acquired Aplastic Anemia is a rare disease with an incidence in British Columbia of 6.9 per million/year in Eastern/Southeastern Asians, 7.3 per million/year in South Asians and 1.7 per million/year in those of White/mixed ethnic descent. Two children presented with mucosal bleeding >4 years after achieving complete remission with immune suppressive therapy (antithymocyte globulin, cyclosporin A and prednisone). Evaluation revealed normal routine coagulation profiles and normal platelet numbers but mildly prolonged bleeding times (patients 8.5 - 11.0 minutes; control 3.0 – 8.0 minutes) and abnormal platelet aggregation as measured by aggregometry (optical and luminescence) after ADP stimulation. The patients had normal aggregation and ATP secretion after stimulation with thrombin (ATP secretion only), collagen, epinephrine, arachidonic acid, and ristocetin (1.125, 1.0, and 0.5 mg/mL concentrations, optical aggregation only) but showed abnormal aggregation with ADP (2.5, 5.0, and 10 μM). An additional 4 aplastic anemia patients were tested >1 year after successful immune suppressive therapy with no bleeding history: 1 of the 4 had the identical defect in platelet aggregation and ATP release after ADP stimulation, with no other defects on aggregometry. All 3 patients with abnormal platelet aggregation were of South or East Asian background, and the 3 with normal aggregation were of Caucasian/mixed ethnicity. Of the patients with an abnormal ADP platelet response, one has subsequently developed ulcerative colitis. Based on these observations we hypothesize that some patients with severe acquired aplastic anemia have an underlying defect in a signaling pathway shared by platelets, T cells, and B cells. ADP-induced signaling in platelets is induced through the surface molecule P2Y12, which is not expressed on lymphocytes. P2Y12 signaling occurs in association with a G protein Galphai2, an important signaling molecule in T and B cells and associated with development of ulcerative colitis in Galphai2 knock out mice. The specific signaling defect in platelets is currently being elucidated in these patients, and the incidence of these defects in aplastic anemia patients must be characterized.

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Skovdahl, Helene, Jan Damås, Atle Granlund, Ann Østvik, Berit Doseth, Torunn Bruland, Tom Mollnes, and Arne Sandvik. "C-C Motif Ligand 20 (CCL20) and C-C Motif Chemokine Receptor 6 (CCR6) in Human Peripheral Blood Mononuclear Cells: Dysregulated in Ulcerative Colitis and a Potential Role for CCL20 in IL-1β Release." International Journal of Molecular Sciences 19, no. 10 (October 20, 2018): 3257. http://dx.doi.org/10.3390/ijms19103257.

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The chemokine C-C motif ligand 20 (CCL20) is increased in the colonic mucosa during active inflammatory bowel disease (IBD) and can be found both in the epithelium and immune cells in the lamina propria. The present study investigated CCL20 and C-C motif Chemokine Receptor 6 (CCR6) in peripheral blood mononuclear cells (PBMCs) (n = 40) from IBD patients and healthy controls, to identify inductors of CCL20 release encountered in a local proinflammatory environment. CCL20 release from PBMCs was increased when activating TLR2/1 or NOD2, suggesting that CCL20 is part of a first line response to danger-associated molecular patterns also in immune cells. Overall, ulcerative colitis (UC) had a significantly stronger CCL20 release than Crohn’s disease (CD) (+242%, p < 0.01), indicating that the CCL20-CCR6 axis may be more involved in UC. The CCL20 receptor CCR6 is essential for the chemotactic function of CCL20. UC with active inflammation had significantly decreased CCR6 expression and a reduction in CCR6+ cells in circulation, indicating chemoattraction of CCR6+ cells from circulation towards peripheral tissues. We further examined CCL20 induced release of cytokines from PBMCs. Stimulation with CCL20 combined with TNF increased IL-1β release from PBMCs. By attracting additional immune cells, as well as inducing proinflammatory IL-1β release from immune cells, CCL20 may protract the inflammatory response in ulcerative colitis.

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Drucker, Daniel J., Bernardo Yusta, Robin P. Boushey, Lorraine DeForest, and Patricia L. Brubaker. "Human [Gly2]GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis." American Journal of Physiology-Gastrointestinal and Liver Physiology 276, no. 1 (January 1, 1999): G79—G91. http://dx.doi.org/10.1152/ajpgi.1999.276.1.g79.

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The pathology of Crohn’s disease and ulcerative colitis is characterized by chronic inflammation and destruction of the gastrointestinal epithelium. Although suppression of inflammatory mediators remains the principle component of current disease therapeutics, strategies for enhancing repair and regeneration of the compromised intestinal epithelium have not been widely explored. The demonstration that a peptide hormone secreted by the intestinal epithelium, glucagon-like peptide-2 (GLP-2), is a potent endogenous stimulator of intestinal epithelial proliferation in the small bowel prompted studies of the therapeutic efficacy of GLP-2 in CD1 and BALB/c mice with dextran sulfate (DS)-induced colitis. We report here that a human GLP-2 analog (h[Gly2]GLP-2) significantly reverses weight loss, reduces interleukin-1 expression, and increases colon length, crypt depth, and both mucosal area and integrity in the colon of mice with acute DS colitis. The effects of h[Gly2]GLP-2 in the colon are mediated in part via enhanced stimulation of mucosal epithelial cell proliferation. These observations suggest that exploitation of the normal mechanisms used to regulate intestinal proliferation may be a useful adjunct for healing mucosal epithelium in the presence of active intestinal inflammation.

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Halm, Dan R., and Susan Troutman Halm. "Secretagogue response of goblet cells and columnar cells in human colonic crypts." American Journal of Physiology-Cell Physiology 277, no. 3 (September 1, 1999): C501—C522. http://dx.doi.org/10.1152/ajpcell.1999.277.3.c501.

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Crypts of Lieberkühn were isolated from human colon, and differential interference contrast microscopy distinguished goblet and columnar cells. Activation with carbachol (CCh, 100 μM) or histamine (10 μM) released contents from goblet granules. Stimulation with prostaglandin E2(PGE2, 5 μM) or adenosine (10 μM) did not release goblet granules but caused the apical margin of columnar cells to recede. Goblet volume was lost during stimulation with CCh or histamine (∼160 fl/cell), but not with PGE2 or adenosine. Three-quarters of goblet cells were responsive to CCh but released only 30% of goblet volume. Half-time for goblet volume release was 3.7 min. PGE2 stimulated a prolonged fluid secretion that attained a rate of ∼350 pl/min. Columnar cells lost ∼50% of apical volume during maximal PGE2 stimulation, with a half-time of 3.3 min. In crypts from individuals with ulcerative colitis, goblet cells were hypersensitive to CCh for release of goblet volume. These results support separate regulation for mucus secretions from goblet cells and from columnar cells, with control mechanisms restricting total release of mucus stores.

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Halm, Dan R., and Susan Troutman Halm. "Secretagogue response of goblet cells and columnar cells in human colonic crypts1." American Journal of Physiology-Cell Physiology 278, no. 1 (January 1, 2000): C212—C233. http://dx.doi.org/10.1152/ajpcell.2000.278.1.c212.

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Crypts of Lieberkühn were isolated from human colon, and differential interference contrast microscopy distinguished goblet and columnar cells. Activation with carbachol (CCh, 100 μM) or histamine (10 μM) released contents from goblet granules. Stimulation with prostaglandin E2(PGE2, 5 μM) or adenosine (10 μM) did not release goblet granules but caused the apical margin of columnar cells to recede. Goblet volume was lost during stimulation with CCh or histamine (∼160 fl/cell), but not with PGE2 or adenosine. Three-quarters of goblet cells were responsive to CCh but released only 30% of goblet volume. Half-time for goblet volume release was 3.7 min. PGE2 stimulated a prolonged fluid secretion that attained a rate of ∼350 pl/min. Columnar cells lost ∼50% of apical volume during maximal PGE2 stimulation, with a half-time of 3.3 min. In crypts from individuals with ulcerative colitis, goblet cells were hypersensitive to CCh for release of goblet volume. These results support separate regulation for mucus secretions from goblet cells and from columnar cells, with control mechanisms restricting total release of mucus stores.

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Van Assche, Gert, and Paul Rutgeerts. "Physiological Basis for Novel Drug Therapies Used to Treat the Inflammatory Bowel Diseases I. Immunology and therapeutic potential of antiadhesion molecule therapy in inflammatory bowel disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 288, no. 2 (February 2005): G169—G174. http://dx.doi.org/10.1152/ajpgi.00423.2004.

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Adhesion molecules regulate the influx of leukocytes in normal and inflamed gut. They are also involved in local lymphocyte stimulation and antigen presentation within the intestinal mucosa. In intestinal inflammation, many adhesion molecules are upregulated, but α4-integrins most likely hold a key position in directing leukocytes into the inflamed bowel wall. Therapeutic compounds directed against trafficking of leukocytes have been designed and are being developed as a novel class of drugs in the treatment of Crohn's disease and ulcerative colitis. This review deals with the immunological aspects of leukocyte trafficking focused on gut homing of T cells. Second, the changes in adhesion molecules and T cell trafficking during intestinal inflammation are discussed. Finally, we review the clinical data that have been gathered with respect to the therapeutic potential and the safety of antiadhesion molecule treatment. Antegren, or natalizumab, a humanized anti-α4 integrin IgG4 antibody, has been most extensively evaluated and may be close to registration. A more specific humanized α4β7-integrin MLN-02 has shown preliminary clinical efficacy in ulcerative colitis, and both antergren and MLN-02 appear to be very safe. Trials with the anti-ICAM-1 antisense oligonucleotide ISIS-2302 in steroid refractory Crohn's disease have provided conflicting efficacy data. In the near future, some of these novel biological agents may prove valuable therapeutic tools in the management of refractory inflammatory bowel disease, although it is too early to define the patient population that will benefit most from these agents.

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Arnauts, K., C. Lapierre, B. Verstockt, S. Verstockt, P. Sudhakar, S. Vermeire, C. Verfaillie, J. Sabino, and M. Ferrante. "P027 Epithelial cells of patients with ulcerative colitis do not show an increased sensitivity after microbiota stimulation compared to non-IBD controls." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S142—S143. http://dx.doi.org/10.1093/ecco-jcc/jjab076.156.

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Abstract Background Alterations in the intestinal microbiota play a pivotal role in the pathogenesis of Inflammatory Bowel Diseases (IBD). Although there is a lot of interest in restoring dysbiosis, the effects of microbial alterations are not fully understood. In addition, it is known that epithelial cells from IBD patients maintain intrinsic defects1. For that reason, our aim was to unravel if epithelial cells of UC patients are more sensitive towards microbiota stimulation, compared to non-IBD controls. Methods Intestinal organoids of UC patients (n=8) and non-IBD controls (n=8) were grown as monolayers on Transwell inserts. Upon confluency (evaluated by transepithelial electrical resistance (TEER)), monolayers were stimulated for 24 hours with TNF-α (100 ng/ml), IL-1β (20 ng/ml) and Flagellin (1 µg/ml) to mimic inflammation. Fresh fecal samples of a selected donor (n=1, high microbial cell count and presence of selected phyla2) and UC patients (n=3, endoscopic sub-mayo ≥2) were filtered and stored in 0.9% NaCl. Monolayers were stimulated for 6 hours with 3.108 microbial cells (cell count by Flow Cytometry). RNA sequencing was performed by Truseq for Illumina. Differentially expressed genes (DEG) were studied by DESeq2 (FDR <0.05). Results Although TEER measurements indicated a higher epithelial cell permeability upon UC microbiota stimulation in UC patients compared to non-IBD controls (p=0.038; Mann-Whitney; Figure 1), we could not confirm this distinct response based on RNA sequencing data at principal component analysis (PCA). Several epithelial barrier genes were significantly upregulated between UC and non-IBD epithelium at nominal p-value, while only CLDN1 and 18 were significant for FDR <0.05 (Figure 2). Clustering on PCA was driven by microbial treatment and not by epithelial origin (Figure 3). Inflamed monolayers of UC patients showed different baseline characteristics (129 DEG; e.g. HLA-G, MUC2, CLDN1, IL23A, PARP8; Figure 4A), but did not propagate in a different response upon microbiota exposure compared to non-IBD controls. Treatment with microbiota of UC patients (23 DEG; e.g. PARP9, TGFBI, ANXA13) or the selected donor (58 DEG; e.g. CCL5, CLDN18, TGFBI) only induced minor differences between epithelial cell types (Figure 4B). Conclusion We observed no different response in epithelial cells of UC patients towards microbiota stimulation compared to non-IBD epithelial cells on transcriptomic level. Further validation on barrier integrity is needed. We observed no indications that microbial treatment would be less beneficial to UC patients, based on the epithelial cell response. Addition of (patient specific) immune cells will contribute to unraveling host-microbiota interactions in IBD patients. References

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Sun, Peng, Kewen Zhou, Sheng Wang, Ping Li, Sijuan Chen, Guiping Lin, Yan Zhao, and Tinghuai Wang. "Involvement of MAPK/NF-κB Signaling in the Activation of the Cholinergic Anti-Inflammatory Pathway in Experimental Colitis by Chronic Vagus Nerve Stimulation." PLoS ONE 8, no. 8 (August 2, 2013): e69424. http://dx.doi.org/10.1371/journal.pone.0069424.

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Shao, Xiaona, Lei Yang, Keyue Hu, Ruiwei Shen, Qunqun Ye, Xiaogang Yuan, Qiang Zhao, and Jianwei Shen. "Serum Cholinesterases, a Novel Marker of Clinical Activity in Inflammatory Bowel Disease: A Retrospective Case-Control Study." Mediators of Inflammation 2020 (July 14, 2020): 1–7. http://dx.doi.org/10.1155/2020/4694090.

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Background. The aim of our study was to investigate whether serum cholinesterase (ChE) levels were associated with inflammatory bowel disease (IBD). Materials and Methods. We conducted a retrospective case-control study to clarify the relationship between serum ChE levels and IBD that included 142 patients with ulcerative colitis (UC), 60 patients with Crohn’s disease (CD), and 264 healthy controls (HCs). We used ROC curves to evaluate the diagnostic value of serum ChE levels for IBD. Results. Substantially lower serum ChE levels were detected in patients with UC than in HCs (6376 U/L versus 8418 U/L, P<0.001) and in patients with CD than in HCs (5181 U/L versus 8418 U/L, P<0.001). Additionally, patients with CD displayed significantly lower serum ChE levels than patients with UC (5181 U/L versus 6376 U/L, P<0.01). We also found that there was a negative association between serum ChE levels and the Crohn’s Disease Activity Index (CDAI) score of patients with CD (P=0.011) and the Simple Clinical Colitis Activity Index (SCCAI) score of patients with UC (P=0.018). The area under the curve (AUC) for serum ChE for the diagnosis of IBD was 0.826, and the AUCs of serum ChE for the diagnosis of CD and UC were 0.890 and 0.800, respectively. Conclusions. Serum ChE levels have important clinical significance in the diagnosis and assessment of clinical activity in patients with IBD, and the cholinergic anti-inflammatory pathway may provide new ideas for targeted treatment of IBD.

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Cerantola, S., M. Ridolfi, S. Faggin, M. Tegon, G. Bussolaro, E. Salviato, M. Bistoletti, V. Caputi, C. Giaroni, and M. C. Giron. "P093 Crosstalk between Toll-like receptor 4 and enteric serotonergic pathways in a mouse model of dinitrobenzene sulfonic acid-induced colitis." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S182. http://dx.doi.org/10.1093/ecco-jcc/jjz203.222.

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Abstract Background Changes in serotonin (5-HT) levels, anomalies in serotonergic and cholinergic machinery and altered Toll-like receptor 4 (TLR4) expression have been shown in IBD in patients and related animal models. Thus, we aimed to assess the crosstalk of enteric serotonergic system and TLR4 signalling in a mouse model of dinitrobenzene sulfonic acid (DNBS)-induced colitis. Methods Male C57/Bl6 (WT) and TLR4−/− mice (9 ± 2 weeks old; N = 10 mice) were presensitised with 1% dinitrobenzene sulfonic acid (DNBS), and after 1 week was intrarectally instilled with 2.5% DNBS. Small intestine inflammation was measured by disease activity index and histological analysis. Changes in ileal muscle tension were isometrically recorded following: (1) cumulative addition of carbachol (CCh; 0.1–100 µM); (2) electric field stimulation (EFS, 0–40 Hz); (3) 60 mM KCl; (4) 30 μM 5-HT addition with or without 0.1 μM ondansetron (5-HT3R antagonist). Immunofluorescence distribution of the neuronal HuC/D and nNOS and glial GFAP markers were determined in longitudinal-muscle-myenteric plexus whole mounts (LMMPs) by confocal microscopy. Results In WT mice, DNBS treatment altered receptor and not-receptor mediated responses (+120% of Emax to CCh and +103% of contraction to KCl, respectively; p < 0.001, N = 5 mice/group) together with an altered cholinergic neurotransmission (−50% at 10 Hz; p < 0.01, N = 5 mice/group) and 2-fold increase to 30 μM 5-HT-mediated response (p < 0.001, N = 5 mice/group). After DNBS treatment TLR4−/− mice showed a significant increase in excitatory-mediated response (+98% of Emax to CCh; +80% of contraction to KCl; +120% at 10 Hz; p < 0.001, N = 5 mice/group) together with a significant reduction of 30 μM 5-HT-mediated response (−50%, p < 0.001, N = 5 mice/group). These changes were associated to a significant decrease of the total number of HuC/D+ neurons (−44% and −19% for WT DNBS and TLR4 DNBS mice, respectively) together with a 1.3-fold increase in S100b immunofluorescence in WT mice after DNBS treatment. Conclusion These findings not only suggest an important role of TLR4 in small intestine neuromuscular dysfunction during colitis but also provide novel information on the potential benefits of targeting TLR4 in various gut disorders that exhibit aberrant cholinergic and 5-HT signalling.

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Seifarth, C., N. Slavova, C. Degro, K. S. Lehmann, M. E. Kreis, and B. Weixler. "Sacral nerve stimulation in patients with ileal pouch-anal anastomosis." International Journal of Colorectal Disease 36, no. 9 (June 23, 2021): 1937–43. http://dx.doi.org/10.1007/s00384-021-03981-z.

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Abstract Purpose Functional results after proctocolectomy and ileal pouch-anal anastomosis (IPAA) are generally good. However, some patients suffer from high stool frequency or fecal incontinence. Sacral nerve stimulation (SNS) may represent a therapeutic alternative in these patients, but little is known about indication and results. The aim of this study was to evaluate incontinence after IPAA and demonstrate SNS feasibility in these patients. Methods This retrospective study includes patients who received a SNS between 1993 and 2020 for increased stool frequency or fecal incontinence after proctocolectomy with IPAA for ulcerative colitis. Proctocolectomy was performed in a two- or three-step approach with ileostomy closure as the last step. Demographic, follow-up data and functional results were obtained from the hospital database. Results SNS was performed in 23 patients. Median follow-up time after SNS was 6.5 years (min. 4.2–max. 8.8). Two patients were lost to follow-up. The median time from ileostomy closure to SNS implantation was 6 years (min. 0.5–max. 14.5). Continence after SNS improved in 16 patients (69%) with a median St. Marks score for anal incontinence of 19 (min. 4–max. 22) before SNS compared to 4 (0–10) after SNS placement (p = 0.012). In seven patients, SNS therapy was not successful. Conclusion SNS implantation improves symptoms in over two-thirds of patients suffering from high stool frequency or fecal incontinence after proctocolectomy with IPAA. Awareness of the beneficial effects of SNS should be increased in physicians involved in the management of these patients.

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Arnauts, K., B. Verstockt, J. Sabino, S. Vermeire, C. Verfaillie, and M. Ferrante. "OP11 Exposure to an inflammatory mix re-induces inflammation in organoids of ulcerative colitis patients, independent of the inflammatory state of the tissue of origin." Journal of Crohn's and Colitis 14, Supplement_1 (January 2020): S011—S012. http://dx.doi.org/10.1093/ecco-jcc/jjz203.010.

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Abstract Background Patient-derived intestinal organoids provide a powerful tool to unravel mechanisms underlying inflammatory bowel disease (IBD). Recently, we showed that organoids derived from inflamed regions in ulcerative colitis (UC) patients lose their inflammatory phenotype during ex vivo culture and were indistinguishable from organoids of non-inflamed regions in these patients.1 To study UC in an ex vivo model, we hypothesised that inflammation should be re-induced towards levels corresponding to the in vivo situation. In addition, we aimed to elucidate if organoids derived from inflamed regions are more sensitive towards inflammatory stimulation, compared with organoids from non-inflamed regions of UC patients and non-IBD controls. Methods Biopsies were obtained from 8 patients with active UC (endoscopic Mayo score of ≥2), both in inflamed and non-inflamed regions, and in 8 non-IBD controls. Crypts were isolated and cultured as organoids for at least four weeks. Organoids were subjected to a predefined inflammatory mix (MIX: 100 ng/ml TNF-α, 20 ng/ml IL-1β, 1 µg/ml Flagellin) or medium only (CTRL) for 24 h (Figure 1). RNA was extracted from organoids for RNA sequencing by Lexogen QuantSeq for Illumina. Differential gene expression and pathways were studied through DESeq2 and ingenuity pathway analysis (false discovery rate <0.05). Results Prior to inflammatory stimulation, principal component analysis (PCA) demonstrated separate clustering between organoids derived from non-IBD controls and UC patients. Exposure to the inflammatory mix induced transcriptional activation of inflammatory genes (CXCL1, DUOXA2, IL1β, IL8, IL23α, etc., all p < 0.001) and pathways in all conditions (Figure 2). However, organoids of non-IBD controls clustered separate from organoids of UC patients. Within organoids of UC patients (inflamed vs. non-inflamed origin), we observed no differentially expressed genes after inflammatory stimulation but organoids clustered per patient instead (Figure 3). Inflammatory markers in UC organoids reached transcriptional expression levels (CXCL1, CXCL2, IFNGR1, IL1β, DUOXA2, etc.) and activated pathways (antigen presentation, interferon signalling, granulocyte adhesion and diapedesis) similar to those observed in crypts derived from inflamed biopsies. Conclusion Inflammation can efficiently be (re-)induced in organoids from both UC and non-IBD origin. However, a different response was observed between organoids of non-IBD and UC origin. Of note, in UC organoids, the state of inflammation in the source tissue was irrelevant. In conclusion, we showed that it is essential to re-induce inflammation in patient-specific organoids, but there is no need to obtain biopsies from inflamed regions. Reference

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He, Lei, Jie Du, Yinyin Chen, Chunyan Liu, Min Zhou, Sarbani Adhikari, David T. Rubin, Joel Pekow, and Yan Chun Li. "Renin-angiotensin system promotes colonic inflammation by inducing TH17 activation via JAK2/STAT pathway." American Journal of Physiology-Gastrointestinal and Liver Physiology 316, no. 6 (June 1, 2019): G774—G784. http://dx.doi.org/10.1152/ajpgi.00053.2019.

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Previous studies suggest that the renin-angiotensin system (RAS) is a pathogenic factor for colitis. The goal of this study was to elucidate the molecular mechanism whereby angiotensin II (ANG II) promotes colonic inflammation. We found that renin was highly induced in colonic biopsies from patients with ulcerative colitis or Crohn’s disease, and colonic renin and ANG II levels were markedly increased in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis model, indicating that the colonic RAS is activated in colitis. Renin transgenic (RenTg) mice exhibited increased phosphorylation in Janus kinase-2 (JAK2) and signal transducer and activator of transcription1/3 (STAT1/3) within colonic mucosa at baseline and following TNBS induction, suggesting that ANG II promotes colonic inflammation via the JAK2/STAT1/3 pathway. Treatment with pan-JAK inhibitor tofacitinib blocked JAK2 and STAT1/3 phosphorylation, attenuated T helper (TH)1 and TH17 responses, alleviated colitis, and prevented death of RenTg mice in TNBS model. ANG II stimulated JAK2/STAT1/3 phosphorylation in both Jurkat T lymphocytes and HCT116 epithelial cells. In vitro polarization assays demonstrated that ANG II directly promoted TH17 polarization, but not TH1 polarization, via JAK2/STAT1/3. ANG II stimulation of transforming growth factor-β1 (TGFβ1), IL-6, myosin light chain kinase, and p53 upregulated modulator of apoptosis in HCT116 cells was also mediated by JAK2/STAT1/3. These observations suggest that ANG II promotes TH17 polarization directly as well as indirectly by inducing production of TH17-polarizing cytokines (e.g., TGFβ1 and IL-6) from colonic epithelial cells, both via the JAK2/STAT pathway. Therefore, colonic RAS promotes colonic inflammation, at least in part, by stimulating TH17 activation. NEW & NOTEWORTHY This study demonstrates that the local renin-angiotensin system in the colon is activated in colitis development, which promotes mucosal T helper cell activation through the JAK2/STAT pathway. These observations provide molecular evidence that the renin-angiotensin system is a pathogenic factor for the development of inflammatory bowel diseases.

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Vigsnæs, Louise Kristine, Jesper Holck, Anne S. Meyer, and Tine Rask Licht. "In VitroFermentation of Sugar Beet Arabino-Oligosaccharides by Fecal Microbiota Obtained from Patients with Ulcerative Colitis To Selectively Stimulate the Growth of Bifidobacterium spp. and Lactobacillus spp." Applied and Environmental Microbiology 77, no. 23 (October 7, 2011): 8336–44. http://dx.doi.org/10.1128/aem.05895-11.

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ABSTRACTThe potential prebiotic properties of arabino-oligosaccharides (AOS) derived from sugar beet pulp was studied using mixed cultures of human fecal bacteria from patients with ulcerative colitis (UC), in remission or with active disease, and in healthy controls. These results were compared to those for fructo-oligosaccharides (FOS), which are known to have a prebiotic effect. Fermentation studies were carried out using a small-scale static batch system, and changes in the fecal microbial communities and metabolites were monitored after 24 h by quantitative real-time PCR and short-chain fatty acid analysis. With a few minor exceptions, AOS affected the communities similarly to what was seen for FOS. Quantitative real-time PCR revealed thatBifidobacteriumspp. andLactobacillusspp. were selectively increased after fermentation of AOS or FOS by fecal microbiota derived from UC patients. The stimulation of growth ofLactobacillusspp. andBifidobacteriumspp. was accompanied by a high production of acetate and hence a decrease of pH. The fermentation of AOS may help improve the inflammatory conditions in UC patients through stimulation of bacteria eliciting anti-inflammatory responses and through production of acetate. AOS may therefore represent a new prebiotic candidate for reduction of the risk of flare-ups in UC patients. However, human trials are needed to confirm a health-promoting effect.

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Yamamoto, Takeshi, Emi Matsunami, Yuya Kanauchi, Shusaku Hayashi, and Makoto Kadowaki. "Tu1619 Activation of the Cholinergic Anti-Inflammatory Pathway Through Alpha-7 Nicotinic Acetylcholine Receptors Improves Symptoms in Murine Oxazolone-Induced Ulcerative Colitis by Inhibiting Migration of Plasmacytoid Dendritic Cells." Gastroenterology 144, no. 5 (May 2013): S—807—S—808. http://dx.doi.org/10.1016/s0016-5085(13)62988-1.

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Dart, R., I. Zlatareva, P. Irving, and A. Hayday. "DOP02 αEβ7 positive γδ T cells are associated with mucosal healing in Ulcerative Colitis and have a homeostatic immunophenotype." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S042. http://dx.doi.org/10.1093/ecco-jcc/jjab073.041.

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Abstract Background α4β7 blockade is a well-established therapy in ulcerative colitis (UC), acting in part by preventing lymphocyte ingress into the mucosa. The β7 unit of the α4β7 heterodimer is shared by α Εβ7, which is expressed on both tissue resident memory cells and γδ intra-epithelial lymphocytes (IEL). It was hypothesised that targeting both α4- and α Εβ7 might be more efficacious; however mixed results from phase III studies of β7 blockade asks questions of the biological relevance of different α Eβ7 expressing cells. Methods Colonic biopsies were obtained during endoscopy from >40 subjects. Lymphocytes were isolated using short term culture or digested from whole tissue. RNA sequencing was performed on α Εβ7pos and α Εβ7neg colonic γδ T cells from 4 donors and findings were validated by flow cytometry. Results α Εβ7 is widely expressed on TCRαβ CD8 cells and γδ IEL in both non-IBD controls and the uninflamed mucosa in UC, but its expression is significantly reduced on analogous subsets harvested from inflamed UC. On further study, the capacity of TCRαβ CD8 T cells to make TNFα and IFNγ on stimulation is similar between α Εβ7pos and α Εβ7neg cells, whereas in the γδ T cell compartment α Εβ7neg cells produce significantly more pro-inflammatory cytokine than their homeostatic α Εβ7pos counterparts. To examine the cells’ biology further, γδ T cells were isolated according to their α Εβ7 status and RNAseq undertaken. This revealed a distinct signature with α Εβ7neg cells demonstrating an activated phenotype high in markers such as CD18, CD5 and lymphoid homing receptor CCR7 whereas α Εβ7pos cells demonstrate a homeostatic tissue-resident phenotype, expressing immune checkpoints TIGIT and CD101 and gut-homing marker CCR9. On culturing tissue from non-IBD controls in pro-inflammatory cytokines, IL-12 and IL-18, the γδ T cell compartment down-regulated α Εβ7 and TIGIT and upregulated CD18, in part recapitulating a disease phenotype. On examining previously affected mucosa of patients who have achieved mucosal healing, α Eβ7 expression of the γδ T cells returned to a profile resembling non-IBD controls whereas the expression levels in the inflamed mucosa remained predictably low. Conclusion This study demonstrates that α Εβ7 expression is low in active UC but restored in mucosal healing. α Εβ7neg cells are proinflammatory with a distinct phenotype which may in part be recapitulated by inflammatory cytokines in vitro; whereas α Εβ7pos cells demonstrate a homeostatic phenotype, which may both reflect and maintain steady state barrier integrity. Hence in terms of γδ T cells, pharmacological β7 blockade has potential to interfere with the homeostatic roles of α Εβ7 expressing cells while having little effect on a potentially pathogenic subset of tissue α Εβ7neg γδ cells.

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Niesner, Uwe, Inka Albrecht, Marko Janke, Cornelia Doebis, Christoph Loddenkemper, Maria H. Lexberg, Katharina Eulenburg, et al. "Autoregulation of Th1-mediated inflammation by twist1." Journal of Experimental Medicine 205, no. 8 (July 28, 2008): 1889–901. http://dx.doi.org/10.1084/jem.20072468.

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The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.

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Kaunitz, Jonathan D., and Piyush Nayyar. "Bugs, genes, fatty acids, and serotonin: Unraveling inflammatory bowel disease?" F1000Research 4 (October 27, 2015): 1146. http://dx.doi.org/10.12688/f1000research.6456.1.

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The annual incidence of the inflammatory bowel diseases (IBDs) ulcerative colitis and Crohn’s disease has increased at an alarming rate. Although the specific pathophysiology underlying IBD continues to be elusive, it is hypothesized that IBD results from an aberrant and persistent immune response directed against microbes or their products in the gut, facilitated by the genetic susceptibility of the host and intrinsic alterations in mucosal barrier function. In this review, we will describe advances in the understanding of how the interaction of host genetics and the intestinal microbiome contribute to the pathogenesis of IBD, with a focus on bacterial metabolites such as short chain fatty acids (SCFAs) as possible key signaling molecules. In particular, we will describe alterations of the intestinal microbiota in IBD, focusing on how genetic loci affect the gut microbial phylogenetic distribution and the production of their major microbial metabolic product, SCFAs. We then describe how enteroendocrine cells and myenteric nerves express SCFA receptors that integrate networks such as the cholinergic and serotonergic neural systems and the glucagon-like peptide hormonal pathway, to modulate gut inflammation, permeability, and growth as part of an integrated model of IBD pathogenesis. Through this integrative approach, we hope that novel hypotheses will emerge that will be tested in reductionist, hypothesis-driven studies in order to examine the interrelationship of these systems in the hope of better understanding IBD pathogenesis and to inform novel therapies.

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Journal articles on the topic 'Cholinergic stimulation; Ulcerative colitis'

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